An
experimental next-generation integrase inhibitor known as S/GSK1265744 (GSK-744),
being developed by Shionogi-GlaxoSmithKline Pharmaceuticals as a backup to S/GSK1349572
(GSK-572), demonstrated high potency and good tolerability in its first clinical
trial in HIV positive and HIV negative participants, researchers reported at the
49th Interscience Conference on Antimicrobial Agents and
Chemotherapy (ICAAC 2009) last week in San Francisco. The median decrease
in HIV viral load after 10 days of GSK-744 monotherapy was 2.6 log copies/mL,
88% achieved undetectable HIV RNA, and antiviral activity continued after the
last dose.

GSK-Shionogi researchers presented data
for GSK-572, which the company considers its lead integrase inhibitor compound,
at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment
and Prevention (IAS 2009) in July.

At
ICAAC, they presented further data in a series of posters
describing studies of GSK-572 interactions with other antiretroviral drugs (expected
to be clinically insignificant) and metal cations found in certain antacids and
vitamin/mineral supplements (which can be overcome by taking GSK-572 either 2
hours before or 6 hours after these products).

The
research team also introduced the company's "backup" integrase inhibitor
candidate, GSK-744. In laboratory and animal studies, GSK-744 was shown to have
good pharmacokinetic (PK) properties, potent antiviral activity, and a favorable
toxicity profile.

Sherene
Min presented data from the first clinical trial of GSK-744 in humans. In Part
A of this Phase I/IIa study, 18 HIV negative volunteers (including 2 women) were
randomly assigned to receive single escalating doses (5, 10, 25, and 50 mg) of
GSK-744, or else placebo. In Part B, 30 HIV negative individuals (including 1
woman) received multiple escalating doses (5, 10, and 25) of GSK-744, or placebo,
once-daily for 14 days. In Parts A and B, participants used an oral suspension
formulation of GSK-744.

In
Part C, 11 HIV positive participants (all men) were randomly assigned to receive
30 mg GSK-744 monotherapy, or placebo, once-daily for 10 days, followed by 3 days
off treatment, then 14 days of combination antiretroviral therapy (ART). These
participants used a tablet formulation of the drug. In this cohort, the median
CD4 count was approximately 390 cells/mm3. Participants could be either antiretroviral
treatment-naive or treatment experienced but off therapy for at least 3 months.

Researchers
detected no mutations known to confer resistance to the sole approved integrase
inhibitor, raltegravir
(Isentress), or to Gilead's investigational integrase inhibitor elvitegravir.

No
new GSK-744 resistance mutations emerged during the study period.

Based
on these findings, the researchers concluded, "S/GSK1265744 was well tolerated
in healthy and HIV-infected subjects. The PK profile indicated that once-daily
tablet doses of < 30 mg would achieve target therapeutic concentrations.
Potent short-term antiviral efficacy was shown with 30 mg once daily dosing."

On
a conference call following the presentation, Min said that many characteristics
of GSK-744 and GSK-572 were similar, but GSK-744 has a much longer half-life,
nearly double that of GSK-572. She also indicated that the 2 compounds are expected
to have similar interactions with other drugs.